Browsing by Subject "swine"
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Item Interplay between metabolic and myogenic mechanisms in coronary pressure-flow autoregulation(2022-05) Warne, Cooper M.; Tune, Johnathan D.; Dick, Gregory M.; Mallet, Robert T.The local metabolic hypothesis proposes that myocardial oxygen tension, indexed by coronary venous PO2 (CvPO2), determines the degree of coronary pressure-flow autoregulation. Conversely, the myogenic hypothesis proposes that pressure-induced vascular tone, indexed by the pressure at which coronary flow is zero (Pzf), determines autoregulation. My working hypothesis posits that if metabolism predominates, then autoregulation will be directly related to CvPO2, irrespective of reductions in coronary vasomotor tone. Conversely, if a myogenic mechanism predominates, then autoregulation will be directly related to Pzf, regardless of underlying CvPO2. I tested these hypotheses by examining the extent to which exaggeration of the metabolic error signal and attenuation of myogenic tone influences coronary autoregulation. Experiments were performed in anesthetized, open-chest swine in which a coronary artery was cannulated and connected to a servo-controlled roller pump system. This allowed coronary perfusion pressure (CPP) to be incrementally reduced from 140 to 40 mmHg before and during hypoxemia (SO2 ~50%). CvPO2 decreased 13 mmHg and coronary blood flow fell 57% as CPP was reduced. Hypoxemia augmented myocardial oxygen consumption (P < 0.01), increased coronary blood flow (P < 0.0001), and reduced CvPO2 (P < 0.0001) over the same CPP range. Coronary blood flow during hypoxemia maintained myocardial oxygen delivery (P = 0.20). Hypoxemia increased closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (P = 0.02). Gc was inversely correlated to CvPO2 and Pzf, but the correlation was stronger for CvPO2. These findings support that coronary pressure-flow autoregulation is augmented by hypoxemia-induced increases in the local metabolic error signal, regardless of the myogenic tone.Item The Effects of Pyruvate on Oxidative Stress and Myocardial Energetics During Cardioplegic Arrest and Reperfusion(2005-10-01) Knott, E. Marty; Robert T. Mallet; James Caffrey; Jerry SimeckaKnott, E. Marty, The Effects of Pyruvate on Oxidative Stress and Myocardial Energetics During Cardioplegic Arrest and Reperfusion Doctor of Philosophy (Integrative Physiology), October 2005, 118 pp, 1 tables, 17 figures, references, 130 titles. Cardioplegic arrest for bypass surgery imposes global ischemia on the myocardium generating oxyradicals which contribute to post surgical cardiac dysfunction. Early clinical trials have demonstrated that pyruvate-fortified cardioplegia reduces myocardial energy and improves mechanical recovery in patients undergoing elective cardiopulmonary bypass for coronary artery bypass grafting. This study was designed to determine the effects of the natural carbohydrate, pyruvate, on oxidative stress, myocardial energy state, and activities of myocardial metabolic enzymes during and immediately following cardiopulmonary bypass. In the first set of experiments, in situ swine hearts were arrested for 60 min with a 4:1 mixture of blood and crystalloid cardioplegia solution containing 188 mM glucose alone (control) or with additional 23.8 mM lactate or 23.8 mM pyruvate, then reperfused for 3 min with cardioplegia-free blood. Glutathione redox state (GSH/GSSG) and phosphocreatine phosphorylation potential were determine from measurements of myocardial metabolites in left ventricular heart tissue snap frozen at 45 min arrest and 3 min reperfusion. Coronary sinus 8-isoprostane indexed oxidative stress. Pyruvate-fortified cardioplegia decreased oxidative stress, lowering 8-isoporstane content accumulate during arrest and reperfusion. Phosphorylation potential was maintained in all groups during arrest but fell upon reperfusion in the control and lactate and cardioplegia groups. Use of pyruvate cardioplegia during arrest prevented the decline in phosphorylation potential during reperfusion. Pyruvate cardioplegia doubled GSH/GSSG during arrest as compared to lactate, but GSH/GSSG fell during reperfusion all 3 groups. Pyruvate proved to be an effective antioxidant and energy yielding fuel in the setting of carioplegic arrest and reperfusion. From these data, we hypothesized that pyruvate would protect oxidant-sensitive enzymes from inactivation. To test this hypothesis, in situ swine hearts were arrested for 60 min with control cardioplegia and reperfused for 3 min with cardioplegia-free blood alone or with co-infusion c. 12 mM pyruvate. Activities of oxidant-sensitive enzymes, 8-isoprostane content, and energy and antioxidant metabolites were measured in left ventricular myocardium snap-frozen at 45 min arrest and 3 min reperfusion. At 3 min reperfusion, glutathione redox state fell by 70% while 8-isoprostane content increased 75%. Pyruvate administration during reperfusion suppressed oxidative stress, maintained glutathione redox state, and enhanced phosphocreatine phosphorylation potential. Aconitase and glucose 6-phosphate dehydrogenase activities fell during arrest; creatine kinase and phosphofructokinase were inactivated upon reperfusion. Pyruvate protected creatine kinase and reactivated aconitase, which are at least partially mitochondrial enzymes, but did not modify the cytosolic enzymes glucose 6-phosphofructokinase. We conclude that 1) pyruvate-fortified cardioplegia and administration of pyruvate during early perfusion increase the antioxidant state of the heart and reduce oxidative stress occurring as a result of cardioplegic arrest and reperfusion; 2) pyruvate bolsters the myocardial energy state during early reperfusion when administered during cardioplegic arrest or during reperfusion; 3) Cardioplegic arrest and reperfusion inactivated several key metabolic enzymes. Pyruvate administration during reperfusion, the period of most intense oxidative stress, increases the activity of two mitochondrial enzymes during early reperfusion when compared to control. These investigations provide likely mechanisms for the ability of pyruvate-fortified cardioplegia to reduce myocardial injury and improve post-surgical cardiac performance in patients undergoing CPB. More research must be done to solidify pyruvate’s role as a cardioprotective intervention during CPB.